rs142894102

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM5PP5

The NM_000310.4(PPT1):c.329A>G(p.Asn110Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N110K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

PPT1
NM_000310.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:10

Conservation

PhyloP100: 7.83

Publications

6 publications found

Variant links:

Genes affected

PPT1 (HGNC:9325): (palmitoyl-protein thioesterase 1) The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2008]

PPT1 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Myriad Women’s Health

PPT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000310.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-40092077-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3015048.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 1-40092078-T-C is Pathogenic according to our data. Variant chr1-40092078-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196249.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PPT1	NM_000310.4 link	c.329A>G	p.Asn110Ser	missense_variant	Exon 3 of 9	ENST00000642050.2	NP_000301.1
PPT1	NM_001363695.2 link	c.329A>G	p.Asn110Ser	missense_variant	Exon 3 of 8		NP_001350624.1
PPT1	NM_001142604.2 link	c.125-2566A>G		intron_variant	Intron 1 of 5		NP_001136076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPT1	ENST00000642050.2 link	c.329A>G	p.Asn110Ser	missense_variant	Exon 3 of 9		NM_000310.4	ENSP00000493153.1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000187

AC:

AN:

251452

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000195

AC:

285

AN:

1461794

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

156

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.000429

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000194

AC:

216

AN:

1111982

Other (OTH)

AF:

0.000282

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000118

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 1

Pathogenic:3Uncertain:5

Mar 15, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 13, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 110 of the PPT1 protein (p.Asn110Ser). This variant is present in population databases (rs142894102, gnomAD 0.06%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 30541466). ClinVar contains an entry for this variant (Variation ID: 196249). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PPT1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense c.329A>G (p.Asn110Ser) variant in PPT1 gene has been reported previously in multiple individuals affected with PPT1-related disorders (Sheth et al., 2018; Atli et al., 2022; Ozturk et al., 2022). The p.Asn110Ser variant is present with allele frequency of 0.02% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic/ Uncertain Significance (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Asn110Ser in PPT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 110 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2

Mar 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in the heterozygous state in a patient with cognitive impairment, ADHD, and epilepsy in the published literature; however, a second PPT1 variant was not identified (PMID: 33528079); Observed in a homozygous state in a patient with episodic torticollis and sudden cardiac arrest who also harbored another homozygous variant in a gene related to the phenotype (PMID: 35693655); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 30541466, 33528079, Bhavsar2016[CaseReport], 35693655) -

Aug 22, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PPT1 c.329A>G (p.Asn110Ser) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00019 in 1613988 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00019 vs 0.0014), allowing no conclusion about variant significance. c.329A>G has been observed in a homozygous individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Sheth_2018). These data indicate that the variant may be associated with disease. However, this variant has also been observed in a homozygous individual from a consanguineous family affected with Childhood Onset Neurodegeneration with Ataxia and Seizures, yet with a normal PPT1 level, who was also homozygous for a variant in the ADPRHL2 gene (c.235A>C, p.T79P) which may explain the phenotype (Ozturk_2022). In addition, the variant has also been reported as a heterozygous genotype in an individual affected with cognitive impairment, ADHD, and epilepsy (Atli_2022). Thus, these reports do not allow for significant association with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Sheth_2018). The following publications have been ascertained in the context of this evaluation (PMID: 33528079, 30541466, 35693655). ClinVar contains an entry for this variant (Variation ID: 196249). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jul 08, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.329A>G (p.N110S) alteration is located in exon 3 (coding exon 3) of the PPT1 gene. This alteration results from a A to G substitution at nucleotide position 329, causing the asparagine (N) at amino acid position 110 to be replaced by a serine (S). The in silico prediction for the p.N110S alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;.;.;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.50

REVEL

Pathogenic

0.78

Polyphen

1.0

D;.;.;.;.

MVP

0.98

MPC

0.50

ClinPred

0.30

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.68

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over